U.S. patent number 4,070,361 [Application Number 05/789,466] was granted by the patent office on 1978-01-24 for mercaptoalkylsulfonyl proline and pipecolic acid and esters thereof.
This patent grant is currently assigned to E. R. Squibb & Sons, Inc.. Invention is credited to Edward William Petrillo, Jr..
United States Patent |
4,070,361 |
Petrillo, Jr. |
January 24, 1978 |
Mercaptoalkylsulfonyl proline and pipecolic acid and esters
thereof
Abstract
Mercaptoalkylsulfonyl proline derivatives and related compounds
which have the general formula ##STR1## are useful as hypotensive
agents.
Inventors: |
Petrillo, Jr.; Edward William
(Pennington, NJ) |
Assignee: |
E. R. Squibb & Sons, Inc.
(Princeton, NJ)
|
Family
ID: |
25147726 |
Appl.
No.: |
05/789,466 |
Filed: |
April 21, 1977 |
Current U.S.
Class: |
546/248; 548/532;
546/238 |
Current CPC
Class: |
C07D
207/48 (20130101); C07D 211/96 (20130101); A61P
9/12 (20180101) |
Current International
Class: |
C07D
207/48 (20060101); C07D 207/00 (20060101); C07D
211/00 (20060101); C07D 211/96 (20060101); C07D
207/48 (); C07D 211/96 () |
Field of
Search: |
;260/293.85,293.73,326.2,326.47 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Jiles; Henry R.
Assistant Examiner: Schwartz; Richard A.
Attorney, Agent or Firm: Levinson; Lawrence S. Smith; Merle
J.
Claims
What is claimed is:
1. A compound of the formula ##STR6## wherein R and R.sub.2 each is
hydrogen or lower alkyl;
R.sub.1 is hydrogen, lower alkanoyl or benzoyl; and
m is 2 or 3.
2. A compound as in claim 1 wherein R is hydrogen.
3. A compound as in claim 1 wherein m is 2.
4. A compound as in claim 1 wherein m is 3.
5. A compound as in claim 1 wherein R and R.sub.2 each is
hydrogen.
6. A compound as in claim 1 wherein m is 2, R and R.sub.2 each is
hydrogen and R.sub.1 is hydrogen or lower alkanoyl.
7. A compound as in claim 6 wherein the lower alkanoyl group is
acetyl.
8. The L-form of the compound of claim 6.
9. A compound as in claim 6 wherein R.sub.1 is hydrogen.
10. The L-form of the compound of claim 9.
11. A compound as in claim 1 wherein R and R.sub.2 each is
hydrogen, R.sub.1 is benzoyl and m is 2.
12. A compound as in claim 1 wherein R, R.sub.1 and R.sub.2 each is
hydrogen and m is 3.
Description
SUMMARY OF THE INVENTION
This invention relates to new mercaptoalkylsulfonyl proline
derivatives and related compounds which have the formula ##STR2## R
and R.sub.2 each is hydrogen or lower alkyl. R.sub.1 is hydrogen,
lower alkanoyl or benzoyl.
m is 2 or 3.
DETAILED DESCRIPTION OF THE INVENTION
In formula I, the lower alkyl groups represented by R and R.sub.2
are straight or branched chain aliphatic hydrocarbon groups having
up to seven carbon atoms, for example, methyl, ethyl, propyl,
isopropyl, butyl, sec.butyl, t-butyl and the like. The C.sub.1
-C.sub.4 members and especially the C.sub.1 -C.sub.2 members are
preferred.
The lower alkanoyl groups represented by R.sub.1 are the acyl
radicals of the lower fatty acids (up to seven carbons) such as
acetyl, propionyl, butyryl, isobutyryl and the like. Those having
up to four carbons are preferred. Acetyl is especially
preferred.
Preferred embodiments of this invention are those compounds of
formula I wherein m is 2, R and R.sub.2 each is hydrogen and
R.sub.1 is hydrogen or lower alkanoyl, especially hydrogen or
acetyl.
The compounds of this invention are produced by the following
sequence of reactions.
Proline or pipecolic acid, preferably in the form of a lower alkyl
ester in which the alkyl group is easily removed, e.g., the t-butyl
ester, is made to react with a haloalkylsulfonyl halide of the
formula ##STR3## wherein hal represents halogen, preferably
chlorine or bromine, in the presence of an organic base like
triethylamine, N,N-dimethylaniline, N-methylmorpholine or the like
and in an inert organic solvent like dichloromethane, ether,
tetrahydrofuran, dioxane or the like. This coupling reaction yields
a compound of the formula ##STR4##
Reaction of the compound of formula III with a compound of the
formula
in the presence of an organic base like those referred to above and
in an organic solvent like ether, tetrahydrofuran, dioxane, or the
like, yields a product of the formula ##STR5##
Treatment of the product of formula V with trifluoroacetic acid and
anisole, when the alkyl group is t-butyl removes the ester group
and yields the free acid of formula I, i.e., wherein R is
hydrogen.
Treatment of the product of formula V with sodium or potassium
hydroxide in water or a lower alcohol, when the alkyl group is
methyl or other lower alkyl group, and R.sub.1 is lower alkanoyl or
benzoyl, removes the ester group and the R.sub.1 group and yields,
after acidification, the free acid of formula I, i.e., wherein R
and R.sub.1 are hydrogen.
Preferably, the thiol of formula IV is one in which R.sub.1 is
lower alkanoyl or benzoyl, e.g., thiolacetic acid, thiolbenzoic
acid or the like with the result that R.sub.1 in the product of
formula V is lower alkanoyl or benzoyl. A product of formula I
wherein R.sub.1 is hydrogen is obtained by treating the product of
formula V, either before or after the removal of the ester group,
if desired, with ammonia or concentrated ammonium hydroxide
solution.
The proline and pipecolic acid esters are produced as described in
copending application Ser. No. 657,792 filed Feb. 13, 1976 by
Miguel Angel Ondetti and David W. Cushman.
The asterisks in formula I indicate asymmetric carbon atoms (the
carbon atom bearing R.sub.2 is asymmetric when R.sub.2 is other
than hydrogen). Preferred are those compounds wherein the proline
or pipecolic acid portion of the molecule is in the L-form.
Additional experimental details are provided in the illustrative
examples which follow below.
The compounds of this invention are angiotensin converting enzyme
inhibitors and are useful as hypotensive agents, particularly for
the reduction of angiotensin dependent hypertension. By
administering a composition containing one or a combination of
angiotensin converting enzyme inhibitors this invention to a
hypertensive mammal, it intervenes in the renin .fwdarw.
angiotensin I .fwdarw. angiotensin II sequence and the hypertension
is reduced or alleviated.
A single dose, or preferably two to four divided daily doses,
provided on a basis of about 1 to 1000 mg. per kilogram per day and
especially about 10 to 200 mg. per kilogram per day and especially
about 10 to 200 mg. per kilogram per day is appropriate to bring
about a reduction in elevated blood pressure. The animal model
experiments described by Engel., Proc. Soc. Exp. Biol. Med. 143,
483 (1973) provide a valuable guide.
The composition is preferably administered orally, but it can also
be administered subcutaneously, intramuscularly, intravenously or
intraperitoneally. The compound or compounds of formula I can be
formulated as tablets, capsules or elixirs for oral administration.
Sterile solutions or suspensions can be used for parenteral
use.
About 50 to 1500 mg. of a compound or compounds of formula I can be
compounded with a physiologically acceptable vehicle, carrier,
excipient, binder, preservative, stabilizer, flavor, etc., in a
conventional unit dosage form as called for by accepted
pharmaceutical practice. The amount of active substance is selected
so as to provide a dosage in the range indicated.
The following examples are illustrative of the invention and
represent preferred embodiments. All temperatures are in degrees
Celsius.
EXAMPLE 1
1-[[2-(Acetylthio)ethyl]sulfonyl]-L-proline
a. 1-(Vinylsulfonyl)-L-proline t-butyl ester
L-Proline t-butyl ester (6.9 g. 0.04 mol.) and triethylamine (14
ml., 0.1 mol.) are dissolved in 200 ml. of dichloromethane and
stirred in an ice bath while 2-chloroethanesulfonyl chloride (8.2
g., 0.05 mol.) in 100 ml. of dichloromethane is added over 20
minutes. After stirring 2 hours, the mixture is washed with 5%
potassium bisulfate solution, saturated sodium bicarbonate solution
and brine, then evaporated in vacuo. The semi-solid residue is
chromatographed on 350 ml. silica gel using 1:1 ethyl
acetate/hexane as eluant. The main fraction, comprising
1-(vinylsulfonyl)-L-proline t-butyl ester is crystallized from
ether/hexane, m.p. 84.degree.-87.degree. (7.1 g., 68%).
b. 1-[[2-(Acetylthio)ethyl]sulfonyl]-L-proline t-butyl ester
1-(Vinylsulfonyl)-L-proline t-butyl ester (5.0 g., 0.0192 mol.),
triethylamine (2.8 ml., 0.02 mol.) and thiolacetic acid (1.43 ml.,
0.02 mol.) are mixed in 100 ml. of ether and allowed to stand
overnight. The mixture is washed with 5% potassium bisulfate
solution, saturated sodium bicarbonate solution and brine, then
evaporated in vacuo to a yellow oil. The procedure is repeated
using half of the above quantities of triethylamine and thiolacetic
acid. Workup as in part a affords the crude product,
1-[[2-(acetylthio)ethyl]-sulfonyl-L-proline t-butyl ester, which is
filtered through a short silica gel column and crystallized from
ether/hexane, m.p. 46.degree.-50.degree. (2.9 g., 45%)
c. 1-[[2-Acetylthio)ethyl]sulfonyl]-L-proline
The t-butyl ester from part b (2.9 g., 0.0086 mol.) is dissolved in
15 ml. of anisole and 45 ml. of trifluoroacetic acid and let stand
1 hour. The mixture is evaporated in vacuo to a gummy residue which
is taken up in ethyl acetate and treated with a large volume of
hexane. The supernatant is decanted, and the procedure repeated.
The resulting semi-solid is crystallized from ethyl acetate-hexane,
m.p. 63.degree.-67.degree. (1.9 g., 78%). [.alpha.].sub.D = -59.3,
c = 1.07.xi., dimethylformamide.
EXAMPLE 2
1-[(2-Mercaptoethyl)sulfonyl]-L-proline
1-[[2-(Acetylthio)ethyl]sulfonyl]-L-proline (640 mg., 0.0023 mol.)
is dissolved in 5 ml. of water and 5 ml. of concentrated ammonia
and stirred 1 hour under nitrogen. The solution is acidified with
concentrated hydrochloric acid, extracted with ethyl acetate, and
the extracts are washed with brine, dried (MgSO.sub.4) and
evaporated to an oily residue which is applied to a 75 ml. silica
gel column. Elution with 10% acetic acid/benzene affords a main
fraction which is crystallized from chloroform/hexane, to obtain
440 mg. (81%) of 1-[(2-mercaptoethyl)sulfonyl]-L-proline, m.p.
99.degree.-101.degree. [.alpha.].sub.D = -64.3.degree., c =
1.1.xi., dimethylformamide.
EXAMPLE 3
1-[[2-(Benzoylthio)ethyl]sulfonyl]-L-proline
By substituting thiobenzoic acid for thiolacetic acid in the
procedure of Example 1b, and then submitting the product to the
procedure of Example 1c,
1-[[2-(benzoythio)ethyl]sulfonyl]-L-proline is obtained.
EXAMPLE 4
1-[[2-(Acetylthio)ethyl]sulfonyl]-L-pipecolic acid
a. 1-(Vinylsulfonyl)-L-pipecolic acid
By substituting L-pipecolic acid t-butyl ester for the L-proline
t-butyl ester in the procedure of Example 1a,
1-(vinylsufonyl)-L-pipecolic acid t-butyl ester is obtained.
b. 1-[[2-(Acetylthio)ethyl]sulfonyl]-L-pipecolic acid
By substituting 1-(vinylsulfonyl)-L-pipecolic acid t-butyl ester
for the 1-(vinylsulfonyl)-L-proline t-butyl ester in the procedure
of Example 1b, and then submitting the product to the procedure of
Example 1c, 1-[[2-acetylthio)-ethyl]sulfonyl]-L-pipecolic acid
t-butyl ester and 1-[[2-(acetylthio)ethyl]sulfonyl]-L-pipecolic
acid are obtained.
EXAMPLE 5
1-[(2-Mercaptoethyl)sulfonyl]-L-pipecolic acid
By substituting 1-[[2-(acetylthio)ethyl]sulfonyl]-L-pipecolic acid
for the 1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline in the
procedure of Example 2, 1-[(2-mercaptoethyl)-sulfonyl]-L-pipecolic
acid is obtained.
EXAMPLE 6
1-[[2-(Benzoylthio)ethyl]sulfonyl]-L-pipecolic acid
By substituting 1-(vinylsulfonyl)-L-pipecolic acid t-butyl ester
for the 1-(vinylsulfonyl)-L-proline t-butyl ester in the procedure
of Example 3, 1-[[2-benzoylthio)ethyl]-sulfonyl]-L-pipecolic acid
is obtained.
EXAMPLE 7
1-[[2-(Acetylthio)-1-methylethyl]sulfonyl]-L-proline
a. 1-(2-Propenylsulfonyl)-L-proline t-butyl ester
By substituting 1-chloro-2-propanesulfonyl chloride for the
2-chloroethanesulfonyl chloride in the procedure of Example 1a,
1-(2-propenylsulfonyl)-L-proline t-butyl ester is obtained.
b. 1-[[2-(Acetylthio)-1-methylethyl]sulfonyl]-L-proline
By substituting 1-[2-propenylsulfonyl]-L-proline t-butyl ester for
the 1-(vinylsulfonyl)-L-proline t-butyl ester in the procedure of
Example 1b, and then submitting the product to the procedure of
Example 1c, 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-proline
t-butyl ester and
1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-proline are
obtained.
EXAMPLE 8
1-[(2-Mercapto-1-methylethyl)sulfonyl]-L-proline
By substituting
1-[[2-(Acetylthio)-1-methylethyl]-sulfonyl]-L-proline for the
1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline in the procedure of
Example 2, 1-[2-mercapto-1-methylethyl)sulfonyl]-L-proline is
obtained.
EXAMPLE 9
1-[[2-(Benzoylthio)-1-methylethyl]sulfonyl]-L-proline
By substituting 1-(2-propenylsulfonyl)-L-proline t-butyl ester for
the 1-(vinylsulfonyl)-L-proline t-butyl ester in the procedure of
Example 3, 1-[[2-(benzoylthio)-1-methylethyl]sulfonyl]-L-proline is
obtained.
EXAMPLE 10
1-[[2-(Acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic acid
a. 1-(2-Propenylsulfonyl)-L-pipecolic acid t-butyl ester
By substituting 1-chloro-2-propanesulfonyl chloride for the
2-chloroethanesulfonyl chloride and L-pipecolic acid t-butyl ester
for L-proline t-butyl ester in the procedure of Example 1a,
1-(2-propenylsulfonyl)-L-pipecolic acid t-butyl ester is
obtained.
b. 1-[[2-(Acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic acid
By substituting 1-(2-propenylsulfonyl)-L-pipecolic acid t-butyl
ester for the 1-(vinylsulfonyl)-L-proline t-butyl ester in the
procedure of Example 1b, and then submitting the product to the
procedure of Example 1c,
1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic acid t-butyl
ester and 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic
acid are obtained.
EXAMPLE 11
1-[(2-Mercapto-1-methylethyl)sulfonyl]-L-pipecolic acid
By substituting
1-[[2-(acetylthio)-1-methylethyl]-sulfonyl]-L-pipecolic acid for
the 1-[[2-(acetylthio)ethyl]-sulfonyl]-L-proline in the procedure
of Example 2, 1-[(2-mercapto-1-methylethyl)sulfonyl]-L-pipecolic
acid is obtained.
* * * * *